Abstract
The innate immune system relies on families of pattern recognition receptors (PRRs) that detect distinct conserved molecular motifs from microbes to initiate antimicrobial responses. Activation of PRRs triggers a series of signaling cascades, leading to the release of pro-inflammatory cytokines, chemokines and antimicrobials, thereby contributing to the early host defense against microbes and regulating adaptive immunity. Additionally, PRRs can detect perturbation of cellular homeostasis caused by pathogens and fine-tune the immune responses. Among PRRs, nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) have attracted particular interest in the context of cellular stress-induced inflammation during infection. Recently, mechanistic insights into the monitoring of cellular homeostasis perturbation by NLRs have been provided. We summarize the current knowledge about the disruption of cellular homeostasis by pathogens and focus on NLRs as innate immune sensors for its detection. We highlight the mechanisms employed by various pathogens to elicit cytoskeleton disruption, organelle stress as well as protein translation block, point out exemplary NLRs that guard cellular homeostasis during infection and introduce the concept of stress-associated molecular patterns (SAMPs). We postulate that integration of information about microbial patterns, danger signals, and SAMPs enables the innate immune system with adequate plasticity and precision in elaborating responses to microbes of variable virulence.
Highlights
Nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) are a group of evolutionarily conserved pattern recognition receptors (PRRs) critical for microbial recognition and host defense
Detecting pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) appears insufficient for accurate identification of pathogens by the immune system
PAMPs are present in commensal, pathobionts, and pathogenic microorganisms
Summary
Nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) are a group of evolutionarily conserved pattern recognition receptors (PRRs) critical for microbial recognition and host defense. 22 NLRs have been identified in humans and 34 distinct ones in mice They have a common molecular organization comprising a subclass-specific N-terminal effector domain, a central NOD domain, and C-terminal leucine-rich repeats (LRRs) that bind to pathogen-associated molecular patterns (PAMPs). Lipopolysaccharide triggers an alternative inflammasome involving the Toll-like receptor 4 (TLR4)-RIP1-Caspase-8 signaling upstream of NLRP3, which is unique to human monocytes [21]. These examples illustrate the necessity for a careful consideration of potential similarities and differences in NLR biology across species. We propose that in addition to PAMP sensing, NLRs detect stress-associated molecular patterns (SAMPs), allowing for the discrimination of pathogens from harmless microbes. Cellular stress as a trigger and regulator of host antimicrobial defense will be discussed in the context of infection with various pathogenic microbes ranging from viruses to protozoans
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